Induction of Pluripotency

  • Corey Heffernan
  • Jun Liu
  • Huseyin Sumer
  • Luis F. Malaver-Ortega
  • Rajneesh Verma
  • Edmund Carvalho
  • Paul J. VermaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 786)


The molecular and phenotypic irreversibility of mammalian cell differentiation was a fundamental principle of developmental biology at least until the 1980s, despite numerous reports dating back to the 1950s of the induction of pluripotency in amphibian cells by nuclear transfer (NT). Landmark reports in the 1980s and 1990s in sheep progressively challenged this dogmatic assumption; firstly, embryonic development of reconstructed embryos comprising whole (donor) blastomeres fused to enucleated oocytes, and famously, the cloning of Dolly from a terminally differentiated cell. Thus, the intrinsic ability of oocyte-derived factors to reverse the differentiated phenotype was confirmed. The concomitant elucidation of methods for human embryonic stem cell isolation and cultivation presented opportunities for therapeutic cell replacement strategies, particularly through NT of patient nuclei to enucleated oocytes for subsequent isolation of patient-specific (autologous), pluripotent cells from the resulting blastocysts. Associated logistical limitations of working with human oocytes, in addition to ethical and moral objections prompted exploration of alternative approaches to generate autologous stem cells for therapy, utilizing the full repertoire of factors characteristic of pluripotency, primarily through cell fusion and use of pluripotent cell extracts. Stunningly, in 2006, Japanese scientists described somatic cell reprogramming through delivery of four key factors (identified through a deductive approach from 24 candidate genes). Although less efficient than previous approaches, much of current stem cell research adopts this focused approach to cell reprogramming and (autologous) cell therapy. This chapter is a quasi-historical commentary of the various aforementioned approaches for the induction of pluripotency in lineage-committed cells, and introduces transcriptional and epigenetic changes occurring during reprogramming.


Pluripotency SCNT Cell-fusion Cell extract iPSC Epigenetics 


  1. 1.
    Briggs R, King TJ (1952) Transplantation of living nuclei from blastula cells into enucleated frogs’ eggs. PNAS 38:455–463PubMedGoogle Scholar
  2. 2.
    Briggs R, King TJ (1953) Factors affecting the transplantation of nuclei of frog embryonic cells. J Exp Zool 122:485–505Google Scholar
  3. 3.
    Gurdon JB (1962) The transplantation of nuclei between two species of Xenopus. Dev Biol 5:68–83PubMedGoogle Scholar
  4. 4.
    Gurdon JB (1962) Adult frogs derived from the nuclei of single somatic cells. Dev Biol 4:256–273PubMedGoogle Scholar
  5. 5.
    Gurdon JB (1968) Changes in somatic cell nuclei inserted into growing and maturing amphibian oocytes. J Embryol Exp Morphol 20(3):401–414PubMedGoogle Scholar
  6. 6.
    Laskey RA, Gurdon JB (1970) Genetic content of adult somatic cells tested by nuclear transplantation from cultured cells. Nature 228(5278):1332–1334PubMedGoogle Scholar
  7. 7.
    De Robertis EM, Gurdon JB (1977) Gene activation in somatic nuclei after injection into amphibian oocytes. PNAS 74(6):2470–2474PubMedGoogle Scholar
  8. 8.
    McGrath J, Solter D (1984) Inability of mouse blastomere nuclei transferred to enucleated zygotes to support development in vitro. Science 226:1317–1319PubMedGoogle Scholar
  9. 9.
    Willadsen SM (1986) Nuclear transplantation in sheep embryos. Nature 320:63–65PubMedGoogle Scholar
  10. 10.
    Campbell KH, McWhir J, Ritchie WA et al (1996) Sheep cloned by nuclear transfer from a cultured cell line. Nature 380:64–66PubMedGoogle Scholar
  11. 11.
    Wilmut I, Schnieke AE, McWhir J et al (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385:810–813PubMedGoogle Scholar
  12. 12.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedGoogle Scholar
  13. 13.
    Miller R, Ruddle FH (1976) Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell 9:45–55PubMedGoogle Scholar
  14. 14.
    Kikyo N, Wade PA, Guschin D et al (2000) Active remodeling of somatic nuclei in egg cytoplasm by the nucleosomal ATPase ISWI. Science 289:2360–2362PubMedGoogle Scholar
  15. 15.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedGoogle Scholar
  16. 16.
    Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156PubMedGoogle Scholar
  17. 17.
    Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. PNAS 78(12):7634–7638PubMedGoogle Scholar
  18. 18.
    Bongso A, Fong CY, Ng SC et al (1994) Isolation and culture of inner cell mass cells from human blastocysts. Hum Reprod 9(11):2110–2117PubMedGoogle Scholar
  19. 19.
    Thomson JA, Kalishman J, Golos TG et al (1995) Isolation of a primate embryonic stem cell line. PNAS 92(17):7844–7848PubMedGoogle Scholar
  20. 20.
    Thomson JA, Kalishman J, Golos TG et al (1996) Pluripotent cell lines derived from common marmoset (Callithrix jacchus) blastocysts. Biol Reprod 55(2):254–259PubMedGoogle Scholar
  21. 21.
    Stojkovic M, Lako M, Stojkovic P et al (2004) Derivation of human embryonic stem cells from day-8 blastocysts recovered after three-step in vitro culture. Stem Cells 22:790–797PubMedGoogle Scholar
  22. 22.
    Strelchenko N, Verlinsky O, Kukharenko V et al (2004) Morula-derived human embryonic stem cells. Reprod Biomed Online 9:623–629PubMedGoogle Scholar
  23. 23.
    Klimanskaya I, Chung Y, Becker S et al (2006) Human embryonic stem cell lines derived from single blastomeres. Nature 444:481–485PubMedGoogle Scholar
  24. 24.
    Byrne JA, Pedersen DA, Clepper LL et al (2007) Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450:497–502PubMedGoogle Scholar
  25. 25.
    Wilmut I, Beaujean N, de Sousa PA et al (2002) Somatic cell nuclear transfer. Nature 419(6907):583–586PubMedGoogle Scholar
  26. 26.
    Paterson L, DeSousa P, Ritchie W et al (2003) Application of reproductive biotechnology in animals: implications and potentials. Applications of reproductive cloning. Anim Reprod Sci 79:137–143PubMedGoogle Scholar
  27. 27.
    Takahashi S, Ito Y (2004) Evaluation of meat products from cloned cattle: biological and biochemical properties. Cloning Stem Cells 6:165–171PubMedGoogle Scholar
  28. 28.
    Tome D, Dubarry M, Fromentin G (2004) Nutritional value of milk and meat products derived from cloning. Cloning Stem Cells 6:172–177PubMedGoogle Scholar
  29. 29.
    Rudenko L, Matheson JC (2007) The US FDA and animal cloning: risk and regulatory approach. Theriogenology 67:198–206PubMedGoogle Scholar
  30. 30.
    Rudenko L, Matheson JC, Sundlof SF (2007) Animal cloning and the FDA – the risk assessment paradigm under public scrutiny. Nat Biotechnol 25:39–43PubMedGoogle Scholar
  31. 31.
    Rideout WM 3rd, Hochedlinger K, Kyba M et al (2002) Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 109:17–27PubMedGoogle Scholar
  32. 32.
    Sumer H, Liu J, Ta PA et al (2009) Somatic cell nuclear transfer: pros & cons. J Stem Cells 4:85–94PubMedGoogle Scholar
  33. 33.
    French AJ, Adams CA, Anderson LS et al (2008) Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts. Stem Cells 26:485–493PubMedGoogle Scholar
  34. 34.
    Li J, Liu X, Wang H et al (2009) Human embryos derived by somatic cell nuclear transfer using an alternative enucleation approach. Cloning Stem Cells 11:39–50PubMedGoogle Scholar
  35. 35.
    Stojkovic M, Stojkovic P, Leary C et al (2005) Derivation of a human blastocyst after heterologous nuclear transfer to donated oocytes. Reprod Biomed Online 11:226–231PubMedGoogle Scholar
  36. 36.
    Noggle S, Fung HL, Gore A et al (2011) Human oocytes reprogram somatic cells to a pluripotent state. Nature 478:70–75PubMedGoogle Scholar
  37. 37.
    Lucas JJ, Terada N (2003) Cell fusion and plasticity. Cytotechnology 41:103–109PubMedGoogle Scholar
  38. 38.
    Tada M, Tada T, Lefebvre L et al (1997) Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J 16:6510–6520PubMedGoogle Scholar
  39. 39.
    Tada M, Takahama Y, Abe K et al (2001) Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 11:1553–1558PubMedGoogle Scholar
  40. 40.
    Kimura H, Tada M, Nakatsuji N et al (2004) Histone code modifications on pluripotential nuclei of reprogrammed somatic cells. Mol Cell Biol 24:5710–5720PubMedGoogle Scholar
  41. 41.
    Cowan CA, Atienza J, Melton DA et al (2005) Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309:1369–1373PubMedGoogle Scholar
  42. 42.
    Sumer H, Nicholls C, Pinto AR et al (2010) Chromosomal and telomeric reprogramming following ES-somatic cell fusion. Chromosoma 119:9Google Scholar
  43. 43.
    Pralong D, Mrozik K, Occhiodoro F et al (2005) A novel method for somatic cell nuclear transfer to mouse embryonic stem cells. Cloning Stem Cells 7:265–271PubMedGoogle Scholar
  44. 44.
    Sumer H, Jones KL, Liu J et al (2009) Transcriptional changes in somatic cells recovered from embryonic stem-somatic heterokaryons. Stem Cells Dev 18:1361–1368PubMedGoogle Scholar
  45. 45.
    Matsumura H, Tad M, Otsuji T et al (2007) Targeted chromosome elimination from ES-somatic hybrid cells. Nat Methods 4:23–25PubMedGoogle Scholar
  46. 46.
    Walev I, Bhakdi SC, Hofmann F et al (2001) Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-O. Proc Natl Acad Sci USA 98:3185–3190PubMedGoogle Scholar
  47. 47.
    Hansis C, Barreto G, Maltry N et al (2004) Nuclear reprogramming of human somatic cells by Xenopus egg extract requires BRG1. Curr Biol 14:1475–1480PubMedGoogle Scholar
  48. 48.
    Gonda K, Kikyo N (2006) Nuclear remodeling assay in Xenopus egg extract. Methods Mol Biol 348:247–258PubMedGoogle Scholar
  49. 49.
    Hakelien AM, Landsverk HB, Robl JM et al (2002) Reprogramming fibroblasts to express T-cell functions using cell extracts. Nat Biotechnol 20:460–466PubMedGoogle Scholar
  50. 50.
    Collas P (2003) Nuclear reprogramming in cell-free extracts. Philos Trans R Soc Lond B Biol Sci 358:1389–1395PubMedGoogle Scholar
  51. 51.
    Taranger CK, Noer A, Sorensen AL et al (2005) Induction of dedifferentiation, genomewide transcriptional programming, and epigenetic reprogramming by extracts of carcinoma and embryonic stem cells. Mol Biol Cell 16:5719–5735PubMedGoogle Scholar
  52. 52.
    Freberg CT, Dahl JA, Timoskainen S et al (2007) Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol Biol Cell 18:1543–1553PubMedGoogle Scholar
  53. 53.
    Han J, Sachdev PS, Sidhu KS (2010) A combined epigenetic and non-genetic approach for reprogramming human somatic cells. PLoS One 5:e12297PubMedGoogle Scholar
  54. 54.
    Neri T, Monti M, Rebuzzini P et al (2007) Mouse fibroblasts are reprogrammed to Oct-4 and Rex-1 gene expression and alkaline phosphatase activity by embryonic stem cell extracts. Cloning Stem Cells 9:394–406PubMedGoogle Scholar
  55. 55.
    Wernig M, Meissner A, Cassady JP et al (2008) c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2:10–12PubMedGoogle Scholar
  56. 56.
    Nakagawa M, Koyanagi M, Tanabe K et al (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26:101–106PubMedGoogle Scholar
  57. 57.
    Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317PubMedGoogle Scholar
  58. 58.
    Boland MJ, Hazen JL, Nazor KL et al (2009) Adult mice generated from induced pluripotent stem cells. Nature 461:91–94PubMedGoogle Scholar
  59. 59.
    Kang L, Wu T, Tao Y et al (2011) Viable mice produced from three-factor induced pluripotent stem (iPS) cells through tetraploid complementation. Cell Res 21:546–549PubMedGoogle Scholar
  60. 60.
    Zhao XY, Li W, Lv Z (2009) iPS cells produce viable mice through tetraploid complementation. Nature 461:86–90PubMedGoogle Scholar
  61. 61.
    Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedGoogle Scholar
  62. 62.
    Park IH, Zhao R, West JA et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146PubMedGoogle Scholar
  63. 63.
    Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920PubMedGoogle Scholar
  64. 64.
    Carey BW, Markoulaki S, Hanna J et al (2009) Reprogramming of murine and human somatic cells using a single polycistronic vector. PNAS 106:157–162PubMedGoogle Scholar
  65. 65.
    Okita K, Nakagawa M, Hyenjong H et al (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322:949–953PubMedGoogle Scholar
  66. 66.
    Soldner F, Hockemeyer D, Beard C et al (2009) Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136:964–977PubMedGoogle Scholar
  67. 67.
    Stadtfeld M, Nagaya M, Utikal J et al (2008) Induced pluripotent stem cells generated without viral integration. Science 322:945–949PubMedGoogle Scholar
  68. 68.
    Dimos JT, Rodolfa KT, Niakan KK et al (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218–1221PubMedGoogle Scholar
  69. 69.
    Ebert AD, Yu J, Rose FF Jr et al (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277–280PubMedGoogle Scholar
  70. 70.
    Park IH, Arora N, Huo H et al (2008) Disease-specific induced pluripotent stem cells. Cell 134:877–886PubMedGoogle Scholar
  71. 71.
    Raya A, Rodriguez-Piza I, Guenechea G et al (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460:53–59PubMedGoogle Scholar
  72. 72.
    Choi KD, Yu J, Smuga-Otto K et al (2009) Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells 27:559–567PubMedGoogle Scholar
  73. 73.
    Schenke-Layland K, Rhodes KE, Angelis E et al (2008) Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages. Stem Cells 26:1537–1546PubMedGoogle Scholar
  74. 74.
    Zhang J, Wilson GF, Soerens AG et al (2009) Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 104:e30–e41PubMedGoogle Scholar
  75. 75.
    Chambers SM, Fasano CA, Papapetrou EP et al (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27:275–280PubMedGoogle Scholar
  76. 76.
    Hirami Y, Osakada F, Takahashi K et al (2009) Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett 458:126–131PubMedGoogle Scholar
  77. 77.
    Chen YF, Tseng CY, Wang HW et al (2011) Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology 55:1193–1203Google Scholar
  78. 78.
    Takayama K, Inamura M, Kawabata K (2011) Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4alpha transduction. Mol Ther 19:400–407PubMedGoogle Scholar
  79. 79.
    Inamura M, Kawabata K, Takayama K et al (2011) Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX. Mol Ther 19:400–407PubMedGoogle Scholar
  80. 80.
    Pasque V, Miyamoto K, Gurdon JB (2010) Efficiencies and mechanisms of nuclear reprogramming. Cold Spring Harb Symp Quant Biol 75:189–200PubMedGoogle Scholar
  81. 81.
    Ben-Shushan E, Sharir H, Pikarsky E et al (1995) A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells. Mol Cell Biol 15:1034–1048PubMedGoogle Scholar
  82. 82.
    Pikarsky E, Sharir H, Ben-Shushan E et al (1994) Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. Mol Cell Biol 14:1026–1038PubMedGoogle Scholar
  83. 83.
    Barnea E, Bergman Y (2000) Synergy of SF1 and RAR in activation of Oct-3/4 promoter. J Biol Chem 275:6608–6619PubMedGoogle Scholar
  84. 84.
    Wang W, Yang J, Liu H et al (2011) Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. PNAS 108:18283–18288PubMedGoogle Scholar
  85. 85.
    Boiani M, Gentile L, Gambles VV et al (2005) Variable reprogramming of the pluripotent stem cell marker Oct4 in mouse clones: distinct developmental potentials in different culture environments. Stem Cells 23:1089–1104PubMedGoogle Scholar
  86. 86.
    Do JT, Han DW, Gentile L et al (2007) Erasure of cellular memory by fusion with pluripotent cells. Stem Cells 25:1013–1020PubMedGoogle Scholar
  87. 87.
    Huangfu D, Osafune K, Maehr R et al (2008) Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26:1269–1275PubMedGoogle Scholar
  88. 88.
    Huangfu D, Maehr R, Guo W et al (2008) Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26:795–797PubMedGoogle Scholar
  89. 89.
    Hanna J, Markoulaki S, Schorderet P et al (2008) Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133:250–264PubMedGoogle Scholar
  90. 90.
    Choi J, Costa ML, Mermelstein CS et al (1990) MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. PNAS 87:7988–7992PubMedGoogle Scholar
  91. 91.
    Hirai H, Tani T, Katoku-Kikyo N et al (2011) Radical acceleration of nuclear reprogramming by chromatin remodeling with the transactivation domain of MyoD. Stem Cells 29:1349–1361PubMedGoogle Scholar
  92. 92.
    Ghosh Z, Wilson KD, Wu Y et al (2010) Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS One 5:e8975PubMedGoogle Scholar
  93. 93.
    Kim K, Doi A, Wen B et al (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:285–290PubMedGoogle Scholar
  94. 94.
    Polo JM, Liu S, Figueroa ME et al (2010) Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol 28:848–855PubMedGoogle Scholar
  95. 95.
    Guenther MG, Frampton GM, Soldner F et al (2010) Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7:249–257PubMedGoogle Scholar
  96. 96.
    Yoshida Y, Takahashi K, Okita K et al (2009) Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5:237–241PubMedGoogle Scholar
  97. 97.
    Esteban MA, Wang T, Qin B et al (2010) Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6:71–79PubMedGoogle Scholar
  98. 98.
    Kaji K, Norrby K, Paca A et al (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458:771–775PubMedGoogle Scholar
  99. 99.
    Woltjen K, Michael IP, Mohseni P et al (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458:766–770PubMedGoogle Scholar
  100. 100.
    Jia F, Wilson KD, Sun N et al (2010) A nonviral minicircle vector for deriving human iPS cells. Nat Methods 7:197–199PubMedGoogle Scholar
  101. 101.
    Fusaki N, Ban H, Nishiyama A et al (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85:348–362PubMedGoogle Scholar
  102. 102.
    Seki T, Yuasa S, Oda M et al (2010) Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7:11–14PubMedGoogle Scholar
  103. 103.
    Kim D, Kim CH, Moon JI et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476PubMedGoogle Scholar
  104. 104.
    Zhou H, Wu S, Joo JY et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384PubMedGoogle Scholar
  105. 105.
    Warren L, Manos PD, Ahfeldt T et al (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:618–630PubMedGoogle Scholar
  106. 106.
    Miyoshi N, Ishii H, Nagano H et al (2011) Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8:633–638PubMedGoogle Scholar
  107. 107.
    Mizuno Y, Chang H, Umeda K et al (2010) Generation of skeletal muscle stem/progenitor cells from murine induced pluripotent stem cells. FASEB J 24(7):2245–2253PubMedGoogle Scholar
  108. 108.
    Wada H, Kojo S, Kusama C et al (2011) Successful differentiation to T cells, but unsuccessful B-cell generation, from B-cell-derived induced pluripotent stem cells. Int Immunol 23(1):65–74PubMedGoogle Scholar
  109. 109.
    Woods NB, Parker AS, Moraghebi R et al (2011) Efficient generation of hematopoietic precursors and progenitors from human pluripotent stem cell lines. Stem Cells 29(7):1158–1164PubMedGoogle Scholar
  110. 110.
    Kasuda S, Tatsumi K, Sakurai Y et al (2011) Expression of coagulation factors from murine induced pluripotent stem cell-derived liver cells. Blood Coagul Fibrinolysis 22(4):271–279PubMedGoogle Scholar
  111. 111.
    Si-Tayeb K, Noto FK, Sepac A et al (2010) Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev Biol 10:81PubMedGoogle Scholar
  112. 112.
    Tokumoto Y, Ogawa S, Nagamune T et al (2010) Comparison of efficiency of terminally differentiation of oligodendrocytes from induced pluripotent stem cells versus embryonic stem cells in vitro. J Biosci Bioeng 109(6):622–628PubMedGoogle Scholar
  113. 113.
    Brennand KJ, Simone A, Jou J et al (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 479(7374):556Google Scholar
  114. 114.
    Czepiel M, Balasubramaniyan V, Schaafsma W et al (2011) Differentiation of induced pluripotent stem cells into functional oligodendrocytes. Glia 59(6):882–892PubMedGoogle Scholar
  115. 115.
    Kim J, Efe JA, Zhu S et al (2011) Direct reprogramming of mouse fibroblasts to neural progenitors. PNAS 108(19):7838–7843PubMedGoogle Scholar
  116. 116.
    Kitazawa A, Shimizu N (2010) Differentiation of mouse induced pluripotent stem cells into neurons using conditioned medium of dorsal root ganglia. N Biotechnol 28(4):326–333Google Scholar
  117. 117.
    Seibler P, Graziotto J, Jeong H et al (2011) Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci 31(16):5970–5976Google Scholar
  118. 118.
    Tucker BA, Park IH, Qi SD et al (2011) Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One 29; 6(4):e18992Google Scholar
  119. 119.
    Zhou L, Wang W, Liu Y et al (2011) Differentiation of induced pluripotent stem cells of swine into rod photoreceptors and their integration into the retina. Stem Cells 29(6):972–980PubMedGoogle Scholar
  120. 120.
    Hu Q, Friedrich AM, Johnson LV et al (2010) Memory in induced pluripotent stem cells: reprogrammed human retinal-pigmented epithelial cells show tendency for spontaneous redifferentiation. Stem Cells 28(11):1981–1991PubMedGoogle Scholar
  121. 121.
    Ohi Y, Qin H, Hong C et al (2011) Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol 13(5):541–549PubMedGoogle Scholar
  122. 122.
    Zhao T, Zhang ZN, Rong Z et al (2011) Immunogenicity of induced pluripotent stem cells. Nature 474(7350):212–215PubMedGoogle Scholar
  123. 123.
    Itzhaki I, Rapoport S, Huber I et al (2011) Calcium handling in human induced pluripotent stem cell derived cardiomyocytes. PLoS One 6:e18037PubMedGoogle Scholar
  124. 124.
    Itzhaki I, Maizels L, Huber I et al (2011) Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471:225–229PubMedGoogle Scholar
  125. 125.
    Moretti A, Bellin M, Welling A et al (2010) Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363:1397–1409PubMedGoogle Scholar
  126. 126.
    Agarwal S, Loh YH, McLoughlin EM et al (2010) Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464:292–296PubMedGoogle Scholar
  127. 127.
    Liu J, Verma PJ, Evans-Galea M, Delatycki M, Michalska A et al (2011) Generation and function of induced-pluripotent stem cell lines from Friedreich ataxia patients. Stem Cell Rev Reports 7(3):703–713Google Scholar
  128. 128.
    Wehrli M, Dougan ST, Caldwell K, O’Keefe L, Schwartz S et al (2000) Arrow encodes an LDL-receptor-related protein essential for Wingless signaling. Nature 407:527–530PubMedGoogle Scholar
  129. 129.
    Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signaling in mice. Nature 407:535–538PubMedGoogle Scholar
  130. 130.
    Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y et al (1996) A new member of the frizzled family from Drosophila functions as a wingless receptor. Nature 382:225–230PubMedGoogle Scholar
  131. 131.
    Tamai K, Semenov M, Kato Y, Spokony R, Liu C et al (2000) LDL-receptor-related proteins in Wnt signal transduction. Nature 407:530–535PubMedGoogle Scholar
  132. 132.
    Bernatik O, Ganji RS, Dijksterhuis JP, Konik P, Cervenka I et al (2011) Sequential activation and Inactivation of Dishevelled in the Wnt/β-Catenin pathway by casein kinases. J Biol Chem 286:10396–10410PubMedGoogle Scholar
  133. 133.
    Zeng X, Huang H, Tamai K, Zhang X, Harada Y et al (2008) Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135:367–375PubMedGoogle Scholar
  134. 134.
    Tamai K, Zeng X, Liu C, Zhang X, Harada Y et al (2004) A mechanism for Wnt coreceptor activation. Mol Cell 13:149–156PubMedGoogle Scholar
  135. 135.
    Grigoryan T, Wend P, Klaus A, Birchmeier W (2008) Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev 22:2308–2341PubMedGoogle Scholar
  136. 136.
    Sato N, Meijer L, Skaltsounis L et al (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10:55–63PubMedGoogle Scholar
  137. 137.
    Grigoryan T, Wend P, Klaus A et al (2008) Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev 22:2308–2341PubMedGoogle Scholar
  138. 138.
    Ogawa K, Nishinakamura R, Iwamatsu Y et al (2006) Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochem Biophys Res Commun 343:159–166PubMedGoogle Scholar
  139. 139.
    Singla DK, Schneider DJ et al (2006) wnt3a but not wnt11 supports self-renewal of embryonic stem cells. Biochem Biophys Res Commun 345:789–795PubMedGoogle Scholar
  140. 140.
    Cai L, Ye Z, Zhou BY et al (2007) Promoting human embryonic stem cell renewal or differentiation by modulating Wnt signal and culture conditions. Cell Res 17:62–72PubMedGoogle Scholar
  141. 141.
    Silva J, Barrandon O, Nichols J et al (2008) Promotion of reprogramming to Ground STATe pluripotency by signal inhibition. PLoS Biol 6:e253PubMedGoogle Scholar
  142. 142.
    Cole MF, Johnstone SE, Newman JJ, Kagey MH, Young RA (2008) Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 22:746–755PubMedGoogle Scholar
  143. 143.
    Tam W-L, Lim CY, Han J, Zhang J, Ang Y-S et al (2008) T-cell factor 3 regulates embryonic stem cell pluripotency and self-renewal by the transcriptional control of multiple lineage pathways. Stem Cells 26:2019–2031PubMedGoogle Scholar
  144. 144.
    Pereira L, Yi F, Merrill BJ (2006) Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol Cell Biol 26:7479–7491PubMedGoogle Scholar
  145. 145.
    Ogawa K, Nishinakamura R, Iwamatsu Y, Shimosato D, Niwa H (2006) Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochem Biophys Res Commun 343:159–166PubMedGoogle Scholar
  146. 146.
    Marson A, Foreman R, Chevalier B, Bilodeau S, Kahn M et al (2008) Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3:132–135PubMedGoogle Scholar
  147. 147.
    Lluis F, Ombrato L, Pedone E, Pepe S, Merrill BJ et al (2011) T-cell factor 3 (Tcf3) deletion increases somatic cell reprogramming by inducing epigenome modifications. Proc Natl Acad Sci USA 108:11912–11917PubMedGoogle Scholar
  148. 148.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776PubMedGoogle Scholar
  149. 149.
    Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767PubMedGoogle Scholar
  150. 150.
    Bray SJ, Takada S, Harrison E, Shen S-C, Ferguson-Smith AC (2008) The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signaling in Drosophila. BMC Dev Biol 8:11PubMedGoogle Scholar
  151. 151.
    Kovall RA (2008) More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 27:5099–5109PubMedGoogle Scholar
  152. 152.
    Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA (2002) Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev 16:1397–1411PubMedGoogle Scholar
  153. 153.
    Wallberg AE, Pedersen K, Lendahl U, Roeder RG (2002) p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Mol Cell Biol 22:7812–7819PubMedGoogle Scholar
  154. 154.
    Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194:237–255PubMedGoogle Scholar
  155. 155.
    Meier-Stiegen F, Schwanbeck R, Bernoth K, Martini S, Hieronymus T et al (2010) Activated Notch1 target genes during embryonic cell differentiation depend on the cellular context and include lineage determinants and inhibitors. PLoS One 5:e11481PubMedGoogle Scholar
  156. 156.
    Chen X, Xu H, Yuan P, Fang F, Huss M et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133:1106–1117PubMedGoogle Scholar
  157. 157.
    Henrique D, Adam J, Myat A, Chitnis A, Lewis J et al (1995) Expression of a delta homologue in prospective neurons in the chick. Nature 375:787–790PubMedGoogle Scholar
  158. 158.
    Henrique D, Hirsinger E, Adam J, Le Roux I, Pourquie O et al (1997) Maintenance of neuroepithelial progenitor cells by Delta-Notch signaling in the embryonic chick retina. Curr Biol 7:661–670PubMedGoogle Scholar
  159. 159.
    Lowell S, Benchoua A, Heavey B, Smith AG (2006) Notch promotes neural lineage entry by pluripotent embryonic stem cells. PLoS Biol 4Google Scholar
  160. 160.
    Jones P, May G, Healy L, Brown J, Hoyne G et al (1998) Stromal expression of Jagged 1 promotes colony formation by fetal hematopoietic progenitor cells. Blood 92:1505–1511PubMedGoogle Scholar
  161. 161.
    Nemir M, Croquelois A, Pedrazzini T, Radtke F (2006) Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling. Circ Res 98:1471–1478PubMedGoogle Scholar
  162. 162.
    Heinrich PC, Behrmann I, Haan S et al (2003) Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochem J 374:1–20PubMedGoogle Scholar
  163. 163.
    Hirai H, Karian P, Kikyo N (2011) Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor. Biochem J 438:11–23PubMedGoogle Scholar
  164. 164.
    Paling NR, Wheadon H, Bone HK et al (2004) Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. J Biol Chem 279:48063–48070PubMedGoogle Scholar
  165. 165.
    Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117:1281–1283PubMedGoogle Scholar
  166. 166.
    Smith AG, Nichols J, Robertson M et al (1992) Differentiation inhibiting activity (DIA/LIF) and mouse development. Dev Biol 151:339–351PubMedGoogle Scholar
  167. 167.
    Matsuda T, Nakamura T, Nakao K et al (1999) STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J 18:4261–4269PubMedGoogle Scholar
  168. 168.
    Williams RL, Hilton DJ, Pease S et al (1988) Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336:684–687PubMedGoogle Scholar
  169. 169.
    Smith AG, Hooper ML (1987) Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells. Dev Biol 121:1–9PubMedGoogle Scholar
  170. 170.
    Niwa H, Burdon T, Chambers I et al (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12:2048–2060PubMedGoogle Scholar
  171. 171.
    Yoshida K, Chambers I, Nichols J et al (1994) Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signaling pathways. Mech Dev 45:163–171PubMedGoogle Scholar
  172. 172.
    Yeh TC, Pellegrini S (1999) The Janus kinase family of protein tyrosine kinases and their role in signaling. Cell Mol Life Sci 55:1523–1534PubMedGoogle Scholar
  173. 173.
    Kisseleva T, Bhattacharya S, Braunstein J et al (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24PubMedGoogle Scholar
  174. 174.
    Stahl N, Farruggella TJ, Boulton TG et al (1995) Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 267:1349–1353PubMedGoogle Scholar
  175. 175.
    Gerhartz C, Heesel B, Sasse J et al (1996) Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation. J Biol Chem 271:12991–12998PubMedGoogle Scholar
  176. 176.
    Ihle JN, Kerr IM (1995) Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet 11:69–74PubMedGoogle Scholar
  177. 177.
    Cimica V, Chen HC, Iyer JK et al (2011) Dynamics of the STAT3 transcription factor: nuclear import dependent on Ran and importin-beta1. PLoS One 6:e20188PubMedGoogle Scholar
  178. 178.
    Liu L, McBride KM, Reich NC (2005) STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc Natl Acad Sci USA 102:8150–8155PubMedGoogle Scholar
  179. 179.
    Chen X, Xu H, Yuan P et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133:1106–1117PubMedGoogle Scholar
  180. 180.
    Bourillot PY, Aksoy I, Schreiber V et al (2009) Novel STAT3 target genes exert distinct roles in the inhibition of mesoderm and endoderm differentiation in cooperation with Nanog. Stem Cells 27:1760–1771PubMedGoogle Scholar
  181. 181.
    Cartwright P, McLean C, Sheppard A et al (2005) LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132:885–896PubMedGoogle Scholar
  182. 182.
    Kristensen DM, Kalisz M, Nielsen JH (2005) Cytokine signaling in embryonic stem cells. APMIS 113:756–772PubMedGoogle Scholar
  183. 183.
    Suzuki A, Raya A, Kawakami Y et al (2006) Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Proc Natl Acad Sci USA 103:10294–10299PubMedGoogle Scholar
  184. 184.
    Boyle K, Zhang JG, Nicholson SE et al (2009) Deletion of the SOCS box of suppressor of cytokine signaling 3 (SOCS3) in embryonic stem cells reveals SOCS box-dependent regulation of JAK but not STAT phosphorylation. Cell Signal 21:394–404PubMedGoogle Scholar
  185. 185.
    Duval D, Reinhardt B, Kedinger C et al (2000) Role of suppressors of cytokine signaling (Socs) in leukemia inhibitory factor (LIF) -dependent embryonic stem cell survival. FASEB J 14:1577–1584PubMedGoogle Scholar
  186. 186.
    Xu J, Wang F, Tang Z et al (2010) Role of leukaemia inhibitory factor in the induction of pluripotent stem cells in mice. Cell Biol Int 34:791–797PubMedGoogle Scholar
  187. 187.
    Nishishita N, Ijiri H, Takenaka C et al (2011) The use of leukemia inhibitory factor immobilized on virus-derived polyhedra to support the proliferation of mouse embryonic and induced pluripotent stem cells. Biomaterials 32:3555–3563PubMedGoogle Scholar
  188. 188.
    Yang J, van Oosten AL, Theunissen TW et al (2010) Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell 7:319–328PubMedGoogle Scholar
  189. 189.
    Graf U, Casanova EA, Cinelli P (2011) The role of the leukemia inhibitory factor (LIF) – pathway in derivation and maintenance of murine pluripotent stem cells. Genes 2:280–297Google Scholar
  190. 190.
    Brambrink T, Foreman R, Welstead G et al (2008) Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2:151–159PubMedGoogle Scholar
  191. 191.
    Wernig M, Legner C, Jacob H et al (2008) A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nat Biotechnol 26:916–924PubMedGoogle Scholar
  192. 192.
    Maherali N, Ahfeldt T, Rigamonti A et al (2008) A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell 3:340–345PubMedGoogle Scholar
  193. 193.
    Hockemeyer D, Soldener F, Cook EG et al (2008) A drug-inducible system for direct reprogramming of human somatic cells to pluripotency. Cell Stem Cell 3:346–353PubMedGoogle Scholar
  194. 194.
    Lowry WE, Richter L, Yachechko R et al (2008) Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA 105:2883–2888PubMedGoogle Scholar
  195. 195.
    Niwa H, Miyajaki J, Smith AG (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24:372–376PubMedGoogle Scholar
  196. 196.
    Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669–681PubMedGoogle Scholar
  197. 197.
    Bernstein BE, Mikkelsen TS, Xie X et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(315):326Google Scholar
  198. 198.
    Mikkelsen TS, Manching KU, Jaffe DB et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–560PubMedGoogle Scholar
  199. 199.
    Meissner A, Mikkelson TS, Hongcang GU et al (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:766–770PubMedGoogle Scholar
  200. 200.
    Meissner A, Wernig M, Jaenisch R (2007) Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 25:1177–1181PubMedGoogle Scholar
  201. 201.
    Rougier N, Bourchis D, Gomes DM et al (1998) Chromosome methylation patterns during mammalian preimplantation development. Genes Dev 12:2108–2113PubMedGoogle Scholar
  202. 202.
    Imamura M, Miura K, Iwabuchi K et al (2006) Transcriptional repression and DNA hypermethylation of a small set of ES cell marker genes in male germline stem cells. BMC Dev Biol 6:34PubMedGoogle Scholar
  203. 203.
    Jones PA, Wolkowich MJ, Rideout WM et al (1990) De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. PNAS 87:6117–6121PubMedGoogle Scholar
  204. 204.
    Humpherys D, Eggan K, Akutsu H et al (2001) Epigenetic instability in ES cells and cloned mice. Science 293:95–97PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Corey Heffernan
    • 1
  • Jun Liu
    • 1
  • Huseyin Sumer
    • 1
  • Luis F. Malaver-Ortega
    • 1
  • Rajneesh Verma
    • 1
  • Edmund Carvalho
    • 1
  • Paul J. Verma
    • 2
    Email author
  1. 1.Reprogramming and Stem Cell Laboratory, Centre for Reproduction and Development, Monash Institute of Medical ResearchMonash UniversityClaytonAustralia
  2. 2.Reproduction GroupSouth Australian Research & Development Institute (SARDI), Turretfield Research CentreRosedaleAustralia

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